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The use of scaffolds for tissue engineering involves aspects of mechanotransduction that are controlled by scaffold properties and structure at the local, cellular scale. For fibrous, electrospun scaffolds, such features include the local fiber stress-strain behavior, fiber density, and undulations in fiber orientation. These serve to provide variations in local stiffness and anisotropy that cannot be quantified through macroscopic testing alone. A combined computational-experimental approach is adopted whereby finite element simulations of electrospun scaffolds are used to link the macroscopic stress-strain response to underlying fiber geometry and fiber stress-strain response. These simulations capture the discrete fiber-straightening, reorientation, and fiber-fiber contact that occurs during scaffold deformation. They can also provide scaffold “Green’s functions” to quantify local response to concentrated forces exerted by cells, enabling extraction of “cellular force footprints” in principle. The present simulations are informed by actual fiber geometries from high-resolution confocal microscopy images and macroscopic stress-strain data. An output is the local fiber stress-strain response, which is notoriously difficult to obtain by direct experimental measurement. The calibrated simulations underscore the highly non-uniform (non-affine) and anisotropic nature of the deformation. They also reveal the scale-dependent nature of mechanical response. The talk concludes with challenges to simulation “scale-up” and other pertinent issues. This work is supported by a Multidisciplinary Team Grant, Institute for Materials Research, The Ohio State University.